Prion diseases are invariably fatal infectious diseases affecting a wide range of animals. These include chronic wating disease (CWD) of deer and elk, scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt-Jacob disease and kuru in humans. CWD appears to be especially contagious, with suspected horizontal transfer efficiency reaching 90% and estimates of infection among mule deer populations in Colorado reaching 20%. Possible transfer to humans, as exhibited for BSE, has not been systematically disproven and the accompanying risk to public health remains. Moreover, if left unchecked, the ecologic and economic impact could be devastating. Our long-term goals include developing mouse models of CWD to elucidate the molecular mechanisms involved in extraneural prion dissemination, accumulation and replication. We also plan to further our understanding of these processes using novel as well as established mouse models of scrapie, with the ultimate goal of developing further CWD models in mice based on these data. Our specific hypothesis states that certain components of the Complement system enable optimal prion capture, replication and neuroinvasion in CWD and scrapie. We derive this hypothesis from 1) previously published data demonstrating that partial or complete depletion of Complement components C1q, C3 and CD21 delays splenic prion accumulation and replication; and impedes or even prevents disease in murine models of scrapie; and 2) previously published data showing significant PrPCWD localization in CD21-expressing lymphoid tissue from deer and 3) our current data that shows murine CD21/35 interacts with PrPSc without its endogenous ligands C3 and C4. We plan to extend this work and initiate new investigations with the following specific aims: 1) Test Complement-deficient Tg(CerPrP) mouse models. 2) Test the horizontal transmissibility of CWD in Tg(cerPrP) mice. 3) Extend our investigation into the role of Complement in peripheral prion pathogenesis using murine scrapie models. Our data strongly suggest that PrPSC can interact with sites on CD21/35 distinct from those that bind C3 cleavage products. We will map these sites by creating CD21/35 truncation mutants and analyzing their ability to bind PrPSc and PrPCWD. PROJECT NARRATIVE Interspecies transmission from BSE-infected cattle in the UK to humans has almost certainly occurred, and has not been disproved for other TSEs, including scrapie and CWD. Determining mechanisms of transmission of scrapie and CWD, which exhibit incredibly efficient Intraspecies transmission, is vital to ensuring the safety of the nation's food supply and, therefore, public health.